Effect of the barrier function of stratum corneum and viable epidermis and dermis on the skin concentration of topically applied chemicals

Three-dimensional cultured skin (3D skin) models have been utilized for in vitro skin permeation tests to evaluate the skin permeation rate and local effects (efficacy and toxicity) of applied chemicals, particularly from the perspective of the 3Rs (reduction, replacement, refinement) approach. The steady-state concentration of applied chemicals at different depths in the viable epidermis and dermis (VED) is affected by their skin permeation parameters, such as permeability coefficient (Kp) and partition coefficient (K) from the donor solution to the skin of the chemicals. In the present study, the steady-state concentration of chemicals in the VED of EpiDerm 606X (EpiDerm) as representative of a 3D skin model were compared with hairless rat skin. The VED concentrations of chemicals in EpiDerm were higher than those in hairless rat skin when a model hydrophilic compound, antipyrine, and a model lipophilic compound, flurbiprofen, were applied, suggesting that the barrier functions of the VED against the whole skin were higher in EpiDerm than in hairless rat skin. When an ester compound, ethyl nicotinate, was applied, the VED concentration of nicotinic acid, a metabolite of ethyl nicotinate, was lower in EpiDerm than in hairless rat skin. These differences in the VED concentrations of applied chemicals might be related to false-positives and -negatives of topical effects evaluated with 3D skin models. It is important to pay particular attention to differences in VED concentration in 3D skin models and real skin when evaluating local efficacy and toxicity using 3D skin models.